WO2012142142A2 - Agonistes des récepteurs de l'adiponectine et procédés d'utilisation - Google Patents

Agonistes des récepteurs de l'adiponectine et procédés d'utilisation Download PDF

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WO2012142142A2
WO2012142142A2 PCT/US2012/033099 US2012033099W WO2012142142A2 WO 2012142142 A2 WO2012142142 A2 WO 2012142142A2 US 2012033099 W US2012033099 W US 2012033099W WO 2012142142 A2 WO2012142142 A2 WO 2012142142A2
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cancer
ala
amino acid
compound
peptide
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WO2012142142A3 (fr
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Laszlo Otvos
Eva Surmacz
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Temple Univ School of Medicine
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Temple Univ School of Medicine
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/5759—Products of obesity genes, e.g. leptin, obese (OB), tub, fat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to adiponectin peptide fragments and adiponectin peptide fragment derivatives, and their use as agonists of the adiponectin receptor.
  • Obesity is an established risk factor for the development of approximately 30 different diseases and disorders, including cardiovascular and inflammation diseases, and cancer. Obesity has been identified as a risk factor for postmenopausal breast cancer and excess fat tissue (especially abdominal) has been associated with worse response to chemotherapy and shorter disease-free survival, regardless of menopausal status.
  • Adiponectin is a cytokine synthesized in and secreted by adipocytes.
  • Adiponectin is elevated in lean individuals and low in obese people.
  • Adiponectin is known to be a beneficial hormone, with clear catabolic effects on a number of metabolic processes, including glucose regulation and fatty acid metabolism.
  • adiponectin has been shown to be a potent negative regulator of cancer cell growth and might play a preventive role against cancer development.
  • Adiponectin is found in human serum at concentrations of 2-20 ⁇ g/ml. Grossmann, ME., Nkhata, KJ., Mizuno, NK., Ray, A., Cleary, MP. (2008) Br J Cancer 98:370-9.
  • Circulating adiponectin levels are inversely correlated with body mass index (BMI); in contrast, serum leptin positively correlates with BMI.
  • BMI body mass index
  • Adiponectin levels are reduced in conditions of insulin resistance and cardiovascular disease, and even appear to precede these disorders. Yamamoto, Y., Hiroshe, H., Saito, I., Nishikai, K., Saruta, T. (2004) J Clin Endocrinol Metab 89:87-90.
  • adiponectin is considered a protective hormone: it exerts anti-diabetic, antiinflammatory and anti-cancer effects.
  • Adiponectin circulates in trimeric, hexameric, and higher order complexes. Fang, X., Sweeney, G. (2006) Biochem Soc Trans 34:798-801. The C-terminal half of the protein representing the globular domain exhibits potent metabolic effects in various tissues.
  • AdipoRl Two adiponectin receptors have been identified, AdipoRl and AdipoR2. Yamauchi, T., Kamon, J., Ito, Y., Tsuchida, A., Yokomizo, T., Kita, S. et al. (2003) Nature 423:762-9.
  • AdipoRl is a high-affinity receptor for globular adiponectin and a low affinity receptor for the full-sized ligand.
  • Both adiponectin receptors are 7- channel integral membrane proteins containing the N-terminal intracellular portion and the C-terminal extracellular portion (an orientation that is exactly the opposite of other G-protein coupled receptors).
  • T-cadherin a unique cadherin molecule, has been characterized as a third adiponectin receptor on vascular endothelial cells and smooth muscle.
  • T-cadherin is just a co-receptor— it does not appear to play a role in direct ligand binding.
  • AdipoRl has 4 very short extracellular domains, 13, 6, 11 and 16 residues, respectively.
  • Adiponectin has a stimulatory effect on the phosphorylation and subsequent inactivation of 5'-AMP-activated protein kinase (AMPK), and on acetyl coenzyme A carboxylase (ACC), which is the downstream substrate of AMPK. Yamauchi et al. (2002) Nature Medicine 8: 1288-95. In addition, adiponectin can stimulate AMPK.
  • AMPK 5'-AMP-activated protein kinase
  • ACC acetyl coenzyme A carboxylase
  • extracellular-signal-regulated kinases 1 and 2 ERK1/2
  • PPAR peroxisome proliferator-activated receptor-
  • JNK stress responsive c-Jun N-terminal kinase
  • STAT3 signal transducer and activator of transcription 3
  • NF-kB nuclear factor-kB
  • adiponectin may exert its biological activity indirectly, through selective sequestration of different growth factors (e.g., basic fibroblast growth factor, platelet-derived growth factor BB, heparin-binding epidermal growth factor) and inhibition of their normal receptor binding. These interactions involve specific oligomeric forms of adiponectin. Barb, D., Williams, CJ., Neuwirth, AK., Mantzoros, CS. (2007) Am J Clin Nutr 86:s858-66. Wang et al. (2005) J Biol Chem 280: 18341-7.
  • growth factors e.g., basic fibroblast growth factor, platelet-derived growth factor BB, heparin-binding epidermal growth factor
  • Adiponectin is thought to counteract the carcinogenic effects of fat-derived factors, including leptin. Cleary MP., Ray, A., Rogozina, OP., Dogan, S., Grossmann, ME. (2009) Front Biosci (Schol Ed) 1 :329-57. Cleary, MP., Grossmann, ME., Ray, A., (2010) Vet Pathol 47:202-13. Jarde, T., Caldefie-chezet, F., Goncalves-Mendes, N., Mishellany, F., Buechler, C, Penault-Llorca, F. et al. (2009) Endocr Relat Cancer 16: 1197-210.
  • adiponectin blocks the Akt kinase and glycogen synthase kinase/p-catenin pathway.
  • adiponectin can also inhibit breast cancer cell migration and invasion. Taliaferro-Smith, L.,
  • Pfeiler G., Treeck, O., Wenzel, G., Goerse, R., Hartmann, A., Schmitz, G. et al. (2009) Maturitas 63:253-6. Tahakata, C, Miyoshi, Y., Irahara, N., Taguchi, T., Tamaki, Y., Noguchi, S. (2007) Cancer Lett 250:229-36.
  • AdipoRl is expressed at higher levels in pre-invasive breast cancer (DCIS) than in invasive lesions.
  • AdipoRl appears to play a more definite role in breast cancer as adiponectin-dependent antiproliferative effects are abolished by siRNA knockdown of AdipoRl ; cell lines expressing AdipoR2, but lacking AdipoRl do not respond to adiponectin with growth inhibition.
  • adiponectin signaling and cancer prevention could involve induction of intracellular metabolic changes similar to those produced by calorie restriction, i.e., activation of intracellular signals such as AMPK and inhibiton of growth and survival pathways Brochu- Gaudreau K, et al. Endocrine 2010, 37(1): 11-32, Pfeiler G et al., Maturitas 2009, 63(3):253-256.
  • pharmacological activation of adiponectin signaling in obese individuals that are refractory to lifestyle modifications could help to restore beneficial pathways normally controlled by this hormone.
  • Akt was inhibited by adiponectin in MDA-MB-231 breast cancer cells, but activated in prostate cancer cells LNCaP. Kim KY et al. Cancer Res 2009, 69(9):4018-4026, Barb D et al., Endocr Relat Cancer 2007, 14(4):995-1005. Moderate STAT3 stimulation by adiponectin was noted in MDA-MB- 231 cells, while the transcription factor was inhibited in DU145 prostate cancer cells.
  • adiponectin/adiponectin receptor-activating domain should constitute appropriate leads for drug development.
  • Such adiponectin receptor agonists should be equipped with enhanced specificity, low toxicity, high stability, superior bioavailability parameters, and low production costs. The present invention addresses and meets these needs.
  • Compounds of the invention are useful as adiponectin receptor agonists.
  • Xaal is Asn or a non-natural amino acid
  • Xaa2 is Gly or a non-natural amino acid
  • Xaa3 is Tyr or a non-natural amino acid
  • Xaa4 is Tyr or a non-natural amino acid
  • Xaa5 is no amino acid, ⁇ -Ala or -AlaNH 2 ;
  • At least one of Xaal, Xaa2, Xaa3, or Xaa4 is a non-natural amino acid
  • X is an optionally present
  • Z is an optionally present 1-10 amino acid peptide
  • Ml is an optionally present single bond or a linking group
  • M2 is an optionally present single bond or a linking group
  • Xaal is D-Asn and Xaa4 is D-Ser.
  • Xaa2 is Nva.
  • Xaa3 is D-Ser.
  • Xaa2 is Nva and Xaa3 is D-Ser.
  • Xaal is D-Asn
  • Xaa2 is Nva
  • Xaa3 is D-
  • Ser, and Xaa4 is D-Ser.
  • Xaa5 is ⁇ -Ala or -AlaNH 2 .
  • the compound of Formula I, or a salt thereof is selected from the group consisting of:
  • ADP 355-P-Ala D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser- -Ala (SEQ ID NO: 4);
  • ADP 355-P-AlaNH 2 D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser- ⁇ - AlaNH 2 (SEQ ID NO: 5);
  • ADP 355-NH 2 D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 (SEQ ID NO: 6)
  • a method of treating an individual suffering from a cellular proliferative disorder comprising administering to the individual an effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the cellular proliferative disorder is selected from the group consisting of hemangiomatosis in newborn, secondary progressive multiple sclerosis, atherosclerosis, chronic progressive myelodegenerative disease,
  • the cellular proliferative disorder is cancer.
  • the cancer is selected from the group consisting of ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, lung cancer, renal cancer, colorectal cancer, skin cancer, brain cancer and leukemia.
  • the invention is also directed to the use in medicine of a compound according to formula I, or a pharmaceutically acceptable salt thereof.
  • the invention is also directed to the use of a compound according to formula I, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treatment of a cellular proliferative disorder, particularly cancer.
  • the invention is also directed to a compound according to formula I, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treatment of a cellular proliferative disorder, particularly cancer.
  • the embodiments of the invention comprise the components and/or steps disclosed herein.
  • the embodiments of the invention consist essentially of the components and/or steps disclosed herein.
  • the embodiments of the invention consist of the components and/or steps disclosed herein.
  • Figure 1A illustrates the growth inhibitory effect of adiponectin peptide "25" i.e. ADP 25-pAlaNH 2 (Asn-Ile-Pro-Gly-Leu-Tyr-Tyr-Phe-Ala-Tyr-pAlaNH 2 ; SEQ ID NO: 7) on the growth of MCF7 cells.
  • ADP 25-pAlaNH 2 Asn-Ile-Pro-Gly-Leu-Tyr-Tyr-Phe-Ala-Tyr-pAlaNH 2 ; SEQ ID NO: 7
  • the effect of the entire globular domain of adiponectin (gAd) is included for comparison.
  • the data are averages from 3 different assays and represent average results +/- SE and were analyzed by Student t-test, p ⁇ 0.05.
  • Figure IB shows a high-resolution structure of the adiponectin monomer bound to ADP 25-PAlaNH 2 . Active site amino acid side-chains are depicted in white.
  • Figure 2 illustrates the effect of ADP 355-NH 2 (D-Asn-Ile-Pro-Nva-Leu- Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 ; SEQ ID NO: 6) on the growth of cancer cells in vitro.
  • Figure 2 A shows the expression of AdipoRl in cancer cell lines MCF-7, MDA-MB-231 and LN18 by Western blot, as described in Example 3.
  • Figure 2B shows the cytostatic activity of peptide ADP 355-NH 2 at 10-100 ⁇ assessed in MCF-7, MDA-MB-231 , and LN18 cancer cell lines, as described in Example 3. Bars represent % growth inhibition relative to untreated cells +/- SE.
  • Figure 3 illustrates the effects of peptide ADP 355-NH 2 on intracellular cell signaling in cancer cells.
  • the effects of ADP 355-NH 2 on signaling pathways in MCF-7, MDA-MB-231 , and LN18 cells at 0-60 minutes of treatment were studied by Western blot, as described in Example 4.
  • the expression of GAPDH was used as determination of protein loading.
  • Figure 4 illustrates the stability of peptide ADP 355-NH 2 in whole mouse blood.
  • the peptide stability was assessed in whole mouse blood after 30 minutes of incubation by mass spectroscopy as described in Example 5.
  • the only pep tide- originated peaks are at 1 109 and 1131 M/z, representing the unmodified peptide and its sodium adduct.
  • Figure 5 illustrates ADP 355-NH 2 energy analysis. Representative energy minimized structures of ADP 25-NH 2 (speckled) and ADP 355-NH 2 (hatched arrows) are overlaid to the conformation of the 153-162 sequence found in adiponectin protein (white).
  • FIG. 6 illustrates expression of AdipoRl in breast cancer cell lines: MDA-MB-231 (lacking estrogen receptor- , and progesterone receptor, and expressing negligible levels of HER2), MCF7 (hormone receptor positive, moderately HER2 -positive) and ZR751 (hormone receptor positive, moderately HER2-positive).
  • AdipoRl (approximately 43 kDa) was detected by Western blot in 100 mg of proteins using anti-AdipoRl antibody (Ab) from Phoenix Pharmaceuticals (in 1 :500 dilution).
  • adiponectin or its globular domain have been shown to exhibit positive effects on various cells and tissues, the development of this cytokine into an acceptable pro-drug is pharmacologically and economically disadvantageous, due to its large size.
  • the inventors have discovered the minimal adiponectin/adiponectin receptor activating domain. This has permitted the design of small peptides or peptidomimetics based on that minimal domain, that act as adiponectin receptor agonists, exhibit high specificity and low toxicity, and can be manufactured at low cost.
  • the compounds of the invention are believed to inhibit the proliferation of tumor cells, and for some compounds, induce cell death.
  • the compounds are believed effective against a broad range of malignancies, including but not limited to the following: ovarian cancer, breast cancer, prostate cancer, lung cancer, renal cancer, colorectal cancer, brain cancer and leukemia.
  • the compounds are also believed useful in the treatment of non-cancer cellular proliferative disorders, including but not limited to the following:
  • hemangiomatosis in newborn, secondary progressive multiple sclerosis, chronic progressive myelodegenerative disease, neurofibromatosis, ganglioneuromatosis, keloid formation, Paget' s disease of the bone, fibrocystic disease of the breast, uterine fibroids, Peyronie's disease, Dupuytren's disease, restenosis and cirrhosis.
  • treat and “treatment” and grammatical equivalents thereof mean administration of a substance to a subject with the purpose to cure, alleviate, relieve, remedy, prevent or ameliorate a disorder, or a disease state secondary to the disorder.
  • adiponectin means a polypeptide that is primarily derived from adipocytes and is an ortholog of the human adiponectin sequence (Genbank accession No. Q15848, residues 1-244) shown employing the one-letter amino acid code in SEQ ID NO: 8:
  • adiponectin variant means a polypeptide that is functionally similar to adiponectin but contains modifications relative to a naturally- occurring adiponectin sequence.
  • globular domain means, in the context of adiponectin, the Clq/TNF-a-like domain and not including the collagen domain. This region can include but is not limited to residues 108-244 relative to human adiponectin (SEQ ID NO: 9).
  • Peptides are defined herein as organic compounds comprising a chain of two or more amino acids covalently joined by peptide bonds. Peptides may be referred to with respect to the number of constituent amino acids, i.e., a dipeptide contains two amino acid residues, a tripeptide contains three, etc.
  • a "peptide” as used in the presently claimed invention is intended to refer to a moiety with a molecular weight of less than 10,000 Daltons.
  • peptidomimetic means a small protein-like chain designed to mimic a peptide.
  • a peptidomimetic may be a backbone modified peptide, any polyamide or other polymeric structure resembling peptides, peptides containing non-natural amino acid residues or a peptide derivative.
  • amino acid as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference.
  • natural amino acids e.g., L-amino acids
  • modified and unusual amino acids e.g., D-amino acids
  • Natural protein occurring amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine.
  • Natural non-protein amino acids include, but are not limited to arginosuccinic acid, citrulline, cysteine sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3 -monoiodo tyrosine, 3,5-diiodotryosine, 3,5,5'- triiodothyronine, and 3,3',5,5'-tetraiodothyronine.
  • Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, 2,4- diaminobutyric acid, homoarginine, N-methyl-arginine, norleucine, N- methylaminobutyric acid, naphthylalanine, phenylglycine, beta-phenylproline, tert- leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, norvaline, 3,4- dehydroproline, ⁇ , ⁇ -dimethylaminoglycine, N-methylaminoglycine, 4- aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)- cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1- aminocyclopen
  • hydrophobic residues and grammatical equivalents means valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, and functional equivalents thereof.
  • polar residues and grammatical equivalents means aspartic acid, asparagine, glutamic acid, glutamine, lysine, arginine, histidine, serine, and functional equivalents thereof.
  • peptide bond means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid.
  • peptide backbone means the chain of atoms of a peptide comprising the carboxamide groups that are the peptide bonds together with the atoms of the amino acids that link the carboxyl and amino groups of the amino acid (usually the a-carbon of an a-aminoacid).
  • derivative as applied to compounds comprising a peptide chain means a compound wherein one or more of the amino, hydroxyl, or carboxyl groups in a side chain of the peptide, or the terminal amino or carboxyl groups, is modified to a derivative functional group.
  • An amino group may be derivatized as an amide (such as an alkyl carboxamide, acetamide), a carbamate (such as an alkyl carbamate, e.g. methyl carbamate or t-butylcarbamate), or a urea.
  • a hydroxyl group may be derivatized as an ester (such as an alkanoate, e.g. acetate, propionate, or an alkanoate, e.g. acetate, propionate, or an alkanoate, e.g. acetate, propionate, or an alkanoate, e.g. acetate, propionate, or an alkanoate, e.g. acetate
  • arenecarboxylate e.g. benzoate
  • a carbamate such as an alkyl carbamate, e.g. methyl carbamate
  • a carbonate such as an alkyl carbonate, e.g. ethyl carbonate.
  • a carboxyl group may be derivatized as an ester (such as an alkyl ester, e.g. ethyl ester) or an amide (e.g. primary carboxamide, an N-alkyl secondary carboxamide, or an N,N- dialkylcarboxamide).
  • derivatives of the peptide will be expected to result in retention of the properties of the parent peptide, either because the incorporation of the derivative group does not change the properties of the peptide, or the derivatizing group is removed in vivo (e.g. via metabolism).
  • Preferred embodiments of the invention are those wherein three or fewer of the amino, carboxyl, and hydroxyl groups, and preferably two or fewer, or one or none, are modified to a derivative functional group.
  • derivative also includes salts, includes salts of derivatives.
  • Natural amino acid is used to refer to an amino acid which exists in nature.
  • amino acids are represented by the full name thereof, by the three-letter code, as well as the one-letter code corresponding thereto, as shown in Table I below.
  • the structure of amino acids and their abbreviations can be found in the chemical literature, such as in Stryer, 1988, “Biochemistry”, 3 rd Ed., W. H.
  • Non-natural amino acid is used to refer to an amino acid which does not exist on its own in nature, but rather, has been synthesized or created by man.
  • non-natural amino acids include iodinated tyrosine, methylated tyrosine, glycosylated serine, glycosylated threonine, azetidine-2-carboxylic acid, 3,4- dehydroproline, perthiaproline, canavanine, ethionine, norleucine, selenomethionine, animohexanoic acid, telluromethionine, homoallylglycine, and
  • Nva corresponds to the non-natural amino acid norvaline, also known as 2(L)-aminopentanoic acid.
  • NvaNH 2 corresponds to 2(L)-aminopentanamide.
  • Acp corresponds to the non-natural amino acid 6-aminocaproic acid, also known as 6-amino-hexanoic acid.
  • AcpNH 2 corresponds to 6-aminocapramide, also known as 6-amino-hexanamide.
  • Dpr(Ac) corresponds to N2(3)-acetyl-diaminopropionic acid.
  • Dbu corresponds to 2,4-diaminobutyric acid.
  • Glc corresponds to glucose.
  • PGlc corresponds to beta-glucose.
  • Ser (Glc) corresponds to serine glycosylated with a beta-glucosyl residue on the alcohol hydroxyl group.
  • Thr(NAcGal) corresponds to threonine glycosylated with an N-acetyl galactosaminyl residue on the alcohol hydroxyl group.
  • Teyr(I 2 ) corresponds to 3,5-diiodotyrosine.
  • N-MeArg corresponds to N-methyl-arginine.
  • PAla corresponds to beta-alanine, also known as 3-aminopropanoic acid.
  • AlaNH 2 corresponds to the amide derivative of beta- alanine, also known as 3-aminopropanamide.
  • (D)-Ser corresponds to D-serine.
  • Ama corresponds to aminopentanoic acid.
  • AlloThr corresponds to allo-threonine, also known as (2S,3S)-2-amino-3-hydroxybutanoic acid.
  • 3Hyp corresponds to 3- hydroxyproline.
  • 4Hyp corresponds to 4-hydroxyproline.
  • hydroxylated acyclic amino acid refers to an acyclic amino acid that contains at least one alcohol hydroxyl group in its structure.
  • Preferred, but non-limiting, examples of hydroxylated acyclic amino acid are serine, (D)-serine, threonine, (D)-threonine, (L)-allo-threonine, (D)-allo-threonine, (L)- isoserine, (D)-isoserine, (L)-P-homoserine, (D)-P-homoserine, (L)-homoserine, and (D)-homoserine.
  • aliphatic amino acid refers to an amino acid which carbon chain is aliphatic in nature.
  • Non-limiting examples of aliphatic amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, valine, Nva, NvaNH 2 , Acp, AcpNH 2 , Dpr(Ac), Dbu, N-MeArg, Ala, pAlaNH 2 , Apa, and AlloThr.
  • Preferred aliphatic amino acids within the present application are Ala, AlaNH 2 , Acp and AcpNH 2 .
  • the term "peptide transduction domain" is used to indicate a peptide, or derivative thereof, that is capable of crossing cell membranes and of directing the transport of a peptide, protein, or molecule associated with the protein transduction domain, from the outside of a cell into the cytoplasm of the cell through the cytoplasmic membrane of the cell.
  • conjugated referring to the linking of two peptides means that the two peptides are covalently linked to one another.
  • the linking may be
  • the linking group may be a peptide chain, an amino acid, or any group having at least two functional groups and capable of forming covalent bond to each of the two peptide chains.
  • acetylated amino acid refers to an amino acid having an acetyl moiety in its side chain.
  • cellular proliferative disorder means a disorder wherein unwanted cell proliferation of one or more subsets of cells in a multicellular organism occurs. In some such disorders, cells are made by the organism at an atypically accelerated rate.
  • isolated means altered or removed from the natural state through the actions of a human being.
  • a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.”
  • An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as a host cell for example.
  • wild type or wild type or “wt” or “native” and grammatical equivalents thereof mean an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations.
  • the wild type sequence means the most prevalent human sequence.
  • the wild type adiponectin nucleic acids and proteins may be a less prevalent human allele or adiponectin nucleic acids and proteins from any number of organisms, including but not limited to rodents (rats, mice, hamsters, guinea pigs, etc.), primates, and farm animals (including sheep, goats, pigs, cows, horses, etc.).
  • Bioly active means that the peptide of the invention have the ability to bind and act as an antagonist to a adiponectin receptor.
  • inhibitor means to suppress or block an activity or function by at least about ten percent relative to a control value. Preferably, the activity is suppressed or blocked by 50% compared to a control value, more preferably by 75%, and even more preferably by 95%.
  • Medical intervention means a set of one or more medical procedures or treatments that are required for ameliorating the effects of, delaying, halting or reversing a disease or disorder of a subject.
  • a medical intervention may involve surgical procedures or not, depending on the disease or disorder in question.
  • a medical intervention may be wholly or partially performed by a medical specialist, or may be wholly or partially performed by the subject himself or herself, if capable, under the supervision of a medical specialist or according to literature or protocols provided by the medical specialist.
  • the language "effective amount” or “therapeutically effective amount” refers to a nontoxic but sufficient amount of the composition used in the practice of the invention that is effective to promote the required growth arrest or killing of cancer cells in a subject, or is effective to treat a weight-loss nutritional disorder in a subject, or is effective to treat osteoporosis in a subject.
  • the desired treatment may be prophylactic and/or therapeutic. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system.
  • An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology of a disease or disorder for the purpose of diminishing or eliminating those signs.
  • additional ingredients includes, but is not limited to, one or more of the following: excipients, surface active agents, dispersing agents, inert diluents, granulating and disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents, preservatives, physiologically degradable compositions such as gelatin, aqueous vehicles and solvents, oily vehicles and solvents, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, buffers, salts, thickening agents, fillers, emulsifying agents, antioxidants, antibiotics, antifungal agents, stabilizing agents and pharmaceutically acceptable polymeric or hydrophobic materials.
  • Container includes any receptacle for holding the pharmaceutical composition.
  • the container is the packaging that contains the pharmaceutical composition.
  • the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition.
  • packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions can contain information pertaining to the compound's ability to perform its intended function, e.g., causing growth arrest or death of cancerous cells in a subject.
  • SEQ ID NO: l is Xaal-Ile-Pro-Xaa2-Leu-Tyr-Xaa3-Phe-Ala-Xaa4- Xaa5, wherein:
  • Xaal is Asn or a non-natural amino acid
  • Xaa2 is Gly or a non-natural amino acid
  • Xaa3 is Tyr or a non-natural amino acid
  • Xaa4 is Tyr or a non-natural amino acid
  • Xaa5 is no amino acid, ⁇ -Ala or P-AlaNH 2 ;
  • At least one of Xaal, Xaa2, Xaa3, or Xaa4 is a non-natural amino acid
  • X is an optionally present
  • Z is an optionally present
  • Ml is an optionally present single bond or a linking group
  • M2 is an optionally present single bond or a linking group
  • Xaal is D-Asn and Xaa4 is D-Ser.
  • Xaa2 is Nva.
  • Xaa3 is D-Ser.
  • Xaa2 is Nva and Xaa3 is D-Ser.
  • Xaal is D-Asn
  • Xaa2 is Nva
  • Xaa3 is D- Ser
  • Xaa4 is D-Ser.
  • the compound of formula I is selected from the group consisting of ADP355, ADP355-pAla, ADP355-pAlaNH 2 and ADP355-NH 2 ; and salts thereof.
  • X or Z is a 1-10 amino acid peptide.
  • the X or Z peptide comprises 9 amino acids.
  • the peptide comprises 8 amino acids.
  • the peptide comprises 7 amino acids.
  • the peptide comprises 6 amino acids.
  • the peptide comprises 5 amino acids.
  • the peptide comprises 4 amino acids.
  • the peptide comprises 3 amino acids.
  • the peptide comprises 2 amino acids.
  • the peptide comprises 1 amino acid.
  • X or Z is a polymer molecule, a lipophilic compound or an peptide transduction domain.
  • the polymer is a linear or branched polyethylene glycol.
  • the polymer has a molecular weight of from 1 kDa to 200 kDa.
  • the polymer has a molecular weight of from 2 kDa to 95 kDa. In yet further embodiments, the polymer has a molecular weight of from 5 kDa to 80 kDa. In yet further embodiments, the polymer has a molecular weight of from 12 kDa to 60 kDa, such as 1240 kDa, 2040 kDa, 5 kDa, 12 kDa or 20 kDa.
  • the X and Z polymer molecules are independently selected.
  • Xaa5 is ⁇ -Ala. According to some embodiments, Xaa5 is P-AlaNH 2 . According to some embodiments, Xaa5 is no amino acid.
  • the polymer molecule is methoxyl PEG maleimide (mPEG(MAL)), methoxyl PEG forked maleimide (mPEG2(MAL)), methoxyl PEG ortho-pyridyldisulfide (mPEG-OPSS), PEG-vinylsulphone, or ortho- pyridyldisulfide-PEG-hydrazide (OPSS-PEG-hydrazide) in combination with methoxyl PEG aldehyde (mPEG-ALD).
  • mPEG(MAL) methoxyl PEG maleimide
  • mPEG2(MAL) methoxyl PEG forked maleimide
  • mPEG-OPSS methoxyl PEG ortho-pyridyldisulfide
  • PEG-vinylsulphone PEG-vinylsulphone
  • OPSS-PEG-hydrazide ortho- pyridyldisulfide-PEG
  • the polymer molecule is selected from the group consisting of 5k-mPEG(MAL), 20k- mPEG(MAL), 40k-mPEG2(MAL), 5k-mPEG-OPSS, lOk-mPEG-OPSS, 20k-mPEG- OPSS, or OPSS-PEG 2 k-hydrazide in combination with mPEG 30 kD-ALD.
  • the compound of Formula I has a C-terminus which comprises an amino acid, for example wherein the C-terminus comprises Z (if present and comprises a peptide or a transduction domain), Xaa5 (if present) or Xaa4, that amino acid is optionally amidated.
  • a peptide for example a dipeptide having two amino acids Xaal and Xaa2
  • a peptide for example a dipeptide having two amino acids Xaal and Xaa2
  • H is part of the free amino terminus of the peptide and OH is part of the free carboxyl terminus of the peptide;
  • the amino acid Xaal, Xaa5 or Xaa4 when Xaa5 is zero amino acid may be conjugated to a lipophilic compound comprising X or Z either directly or by use of a linker.
  • the lipophilic compound may be a natural compound such as a saturated or unsaturated fatty acid, a fatty acid diketone, a terpene, a prostaglandin, a vitamin, a carotenoid or steroid or a synthetic compound such as a carbon acid, an alcohol, an amine and sulphonic acid with one or more alkyl-, aryl-, alkenyl-, or other multiple unsaturated compounds.
  • the conjugation between the amino acid and the lipophilic compound, optionally through a linker may be done according to methods known in the art, e.g. as described by Bodanszky in Peptide Syntesis, John Wiley, New York, 1976 and in WO 96/12505.
  • X or Z is a polymer compound.
  • the hydroxyl end groups of the polymer molecule must be provided in activated form, i.e. with reactive functional groups (for example primary amino groups, hydrazide (HZ), thiol, succinate (SUC), succinimidyl succinate (SS), succinimidyl succinamide (SSA), succinimidyl proprionate (SPA), succinimidyl carboxymethylate (SCM), benzotriazole carbonate (BTC), N-hydroxysuccinimide (NHS), aldehyde,
  • reactive functional groups for example primary amino groups, hydrazide (HZ), thiol, succinate (SUC), succinimidyl succinate (SS), succinimidyl succinamide (SSA), succinimidyl proprionate (SPA), succinimidyl carboxymethylate (SCM), benzotriazole carbonate (BTC), N-hydroxysuccinimide (NHS), aldehyde,
  • reactive functional groups for example primary amino groups, hydrazide (HZ
  • activated PEG polymers include the following linear PEGs: NHS-PEG (e.g. SPA-PEG, succinimidyl succinate proprionate-PEG (SSPA-PEG), SBA-PEG, SS-PEG, SSA- PEG, succinimidyl carbonate-PEG (SC-PEG), succinimidyl glutarate-PEG (SG-PEG), and SCM-PEG and NOR-PEG), BTC-PEG, epoxide-PEG (EPOX-PEG), isocyanate- PEG (NCO-PEG), NPC-PEG, carbonylimidazole-PEG (CDI-PEG), aldehyde-PEG (ALD-PEG), TRES-PEG, VS-PEG, iodo-PEG, and maleimide-PEG (MAL-PEG), and branched PEGs such as
  • the compounds of the invention may be prepared by methods known to the person skilled in the art of peptide and organic synthesis.
  • Peptides of the present invention may be natural peptides, recombinant peptides or synthetic peptides. They may also be chemically synthesized, using, for example, solid phase synthesis methods. Preferred methods of synthesis of compounds of formula I are set forth in Examples 1 and 2 herein. Additionally, peptide transduction domains appended to peptides of the invention may be natural or synthetic peptides, and may be either prepared by isolation from natural sources or may be synthesized.
  • the peptides of the present invention may be synthesized de novo using peptide synthesis methods.
  • the peptide chain is prepared by a series of coupling reactions in which the constituent amino acids are added to the growing peptide chain in the desired sequence.
  • N-protecting groups e.g., the carbobenzyloxy group or the t-butyloxycarbonyl group
  • various coupling reagents e.g., dicyclohexylcarbodiimide or carbonyldiimidazole
  • various active esters e.g., esters of N-hydroxyphthalimide or N-hydroxy-succinimide
  • the various cleavage reagents e.g., trifluoro acetic acid (TFA), HC1 in dioxane, boron tris-(trifluoracetate) and cyanogen bromide
  • reaction in solution with isolation and purification of intermediates are methods well-known to those of ordinary skill in the art.
  • the reaction may be carried out with the peptide either in solution or attached to a solid phase support. In the solid phase method, the peptide is released from the solid phase support following completion of the synthesis.
  • the peptide synthesis method may follow Merrifield solid-phase procedures. See Merrifield, J. Am. Chem. Soc, 1963, 85, 2149-54 and Science, 1965, 50, 178-85. Additional information about the-solid phase synthetic procedure can be obtained from the treatises Solid Phase Peptide Synthesis: A
  • peptides may be prepared utilizing recombinant DNA technology, which comprises combining a nucleic acid encoding peptides of formula I in a suitable vector, inserting the resulting vector into a suitable host cell, recovering the peptide subsequently produced by the host cell, and purifying the polypeptide recovered.
  • recombinant DNA technology comprises combining a nucleic acid encoding peptides of formula I in a suitable vector, inserting the resulting vector into a suitable host cell, recovering the peptide subsequently produced by the host cell, and purifying the polypeptide recovered.
  • the required techniques of recombinant DNA and protein technology are known to the ordinary skilled artisan. General methods for the cloning and expression of recombinant molecules are described in Molecular Cloning by Sambrook et al. (Cold Spring Harbor Laboratories, Second Ed., 1989) and in Current Protocols in Molecular Biology by Ausubel (Wiley and Sons, 1987).
  • the nucleic acid encoding a desired peptide may be operatively linked to one or more regulatory regions. Regulatory regions include promoters,
  • polyadenylation signals polyadenylation signals, translation initiation signals (Kozak regions), termination codons, peptide cleavage sites, and enhancers.
  • the regulatory sequences used must be functional within the cells of the vertebrate in which they are administered.
  • Promoters that may be used in the synthesis of compounds of the present invention include both constitutive promoters and inducible promoters.
  • the promoters may be prokaryotic or eukaryotic, depending on the host.
  • the compounds of the invention may be purified using known techniques, for example preparative HPLC, FPLC, affinity chromatography, as well as other chromatographic methods. Isolated compounds may then be assessed for biological activity according to the methods described herein, as well as by any methods known to the skilled artisan.
  • peptides can be produced by the established procedure of solid phase peptide synthesis. Briefly, this procedure entails the sequential assembly of the appropriate amino acids into a peptide of a desired sequence while the end of the growing peptide is linked to an insoluble support. Usually, the carboxyl terminus of the peptide is linked to a polymer from which it can be liberated upon treatment with a cleavage reagent.
  • the linking group (Ml or M2) for coupling X or Z in a compound of formula I may be any moiety that is at least bifunctional, provided that the resulting link between X or Z and the N-terminal or C-terminal amino acid or non-natural amino acid is stable.
  • Suitable linking groups include bi- and multi-functional alkyl, aryl, aralkyl or peptidic moieties, alkyl, aryl or aralkyl aldehydes acids esters and anhydrides, sulfhydryl or carboxyl groups, such as maleimido benzoic acid derivatives, maleimido propionic acid derivatives and succinimido derivatives or may be derived from cyanuric bromide or chloride, carbonyldiimidazole, succinimidyl esters or sulphonic halides and the like (Fischer et al, U.S. Patent No. 6,472,507, the entire disclosure of which is incorporated herein by reference).
  • the functional groups on the linker moiety may include amino, hydrazino, hydroxyl, thiol, maleimido, carbonyl, and carboxyl groups.
  • the linker group is selected so as to be sufficiently labile (e.g., to enzymatic cleavage by an enzyme present in the targeted tissue) so that it is cleaved following transport of a peptide of the invention, thereby releasing the peptide.
  • labile linkages are described in Low et al, U.S. Patent No. 5,108,921, the entire disclosure of which is incorporated herein by reference.
  • the peptide-active agent delivery system may also dissociate by way of chemical cleavage between the active agent and peptide of the invention. Within the embodiments wherein the linker moiety includes amino acid residues, such cleavage may occur within the linker moiety itself.
  • any amino acid including, but not restricted to, oc-amino acids including, but not restricted to, the proteinogenic amino acids
  • peptide chain may form the link between Xaal and X.
  • linking groups Ml for linking Xaal and a carboxyl group of X include:
  • n is one or greater, preferably one to three
  • each -Z3- is selected from the group consisting of:
  • linking group Ml for linking Xaal and an amino group of the working element include:
  • n is one or greater, preferably one to three;
  • each -Z3- is selected from the group consisting of:
  • linking groups M2 for linking Xaa5 and a carboxyl group of Z include:
  • n is one or greater, preferably one to three
  • each -Z4- is selected from the group consisting of:
  • the link formed by the linking group M2 is between Xaa5 and an amino group of Z (for example the terminal amino group of a peptidic Z or the terminal amino group of a molecular Z)
  • linking group M2 for linking Xaa5 and an amino group of Z include:
  • n is one or greater, preferably one to three;
  • each -Z4- is selected from the group consisting of:
  • the tagging element (which may be X and/or Z) is selected from the group consisting of a transduction domain and a detection label.
  • the compounds of the invention may or may not have the ability to cross the blood brain barrier, depending on their intrinsic properties. Determination of ability of the compounds of the invention to penetrate the blood brain barrier may be easily performed using standard techniques such as those cited in Bernacki et al., 2008, Pharmacol. Rep. 60 (5): 600-22.
  • the activity of the compound of the invention may not be felt in receptors located in various parts of the brain. This may limit the action of the compound to those receptors located outside of the central nervous system.
  • the compound of the invention finds use in the treatment of cancers that occur in peripheral systems, such as breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, ovarian cancer, endometric cancer and lung cancer.
  • the activity of the compound may be felt in receptors located in various parts of the brain.
  • the compound may be active against receptors located both inside and outside the central nervous system.
  • the compound of the invention finds use in the treatment of weight-loss nutritional disorders, such as cachexia and wasting, and cancers, such as glioma, in addition to peripheral cancers such as breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, ovarian cancer, endometric cancer and lung cancer.
  • Peptide transduction domains useful in the invention include, but are not limited to, a Tat peptide from HIV glycoprotein 120, a transportan, polyarginine, polylysine, and proline-arginine rich antibacterial peptides such as pyrrhocoricin, as set forth in U.S. Patent No. 7,015,309, incorporated herein by reference in its entirety.
  • a peptide transduction domain is polycationic.
  • the compounds of the invention may also benefit from the property of being easily monitored or detected in vitro or in vivo.
  • the monitoring or detection of the compounds of the invention would allow one skilled in the art to identify whether and/or which cells under observation contain adiponectin receptors, and to follow the binding of the compounds of the invention to such adiponectin receptor-positive cells.
  • the monitoring or detection of the compounds of the invention would allow one skilled in the art to determine whether/or which the tissues under observation contain adiponectin-receptor positive cells and to evaluate the biodistribution of the peptides dose in an individual.
  • the compound of the invention binds to the adiponectin receptor-positive cell and the binding is evaluated by measuring the change in a specified physical property of the compound of the invention once it binds to the cell.
  • Non-limiting physical properties contemplated within the invention include UV-vis absorption; IR absorption; 1H, 13 C or 15 N NMR signals or relaxation; fluorescence; and magnetic properties.
  • the ability of detecting a compound of the invention, in either an unbound or a bound form, may be enhanced when the compound of the invention comprises a detection label as the tagging element (X and/or Z).
  • a detection label as the tagging element (X and/or Z).
  • cells that present adiponectin receptors on their surfaces may bind the peptide of the invention and the detection label may be used to monitor the binding or identify the position of the adiponectin receptor-containing cells.
  • the method used to monitor such phenomena is dependent on the specific nature of the detection label. In the case that the detection label is a fluorescent label, fluorescent detection would be favored.
  • the compound of the invention binds to the adiponectin receptor- positive cell and the binding is evaluated by measuring the change in fluorescence of the compound of the invention upon binding to the cell,
  • X and/or Z may comprise a protein transduction domain.
  • a protein transduction domain is a peptide that is capable of crossing cell membranes and of directing the transport of a peptide, protein, or molecule associated with the protein transduction domain; from the outside of a cell into the cytoplasm of the cell through the cytoplasmic membrane of the cell.
  • Protein transduction domains have been the subject of considerable interest and investigation because of their ability, through conjugation to other compounds, to facilitate transport of the conjugated compound into the cell, and as a result a substantial body of literature has been published. See, for example, Handbook of Cell-Penetrating Peptides, by Ulo Langel (Editor) (CRC Press, 2 nd Edition, 2006). Cell-Penetrating Peptides: Process and Applications, by Ulo Langel (Editor) (CRC Press, 1 st Edition, 2002); E.L. Snyder, et al., “Cell-penetrating Peptides in Drug Delivery", Pharm. Res., 2004, 27(3), 389-93. A.J.M. Beerens, et al., "Protein
  • amino acid sequences that may be incorporated in, or used as, protein transduction domains are those shown in Table II.
  • Trp Glu Ala Lys Leu Ala Lys Ala Leu Ala Lys Ala KALA
  • Non-limiting examples of detection labels are fluorescent labels, such as cyanin derivatives (Bioconj. Chem. 1993, 4, 105-11 1), coumarin derivatives such as aminomethylcoumarin (Histochem. J. 1986, 8(9): 497-9), Lucifer Yellow (Invitrogen, Carlsbad, CA), dansyl chloride and derivatives (Methods Mol. Biol. 1994, 32: 329- 34), phycobiliproteins (such as B-phycoerythrin, R-phycoerythrin and
  • Alexa Fluor dyes such as Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 647, Alexa Fluor 546, Alexa Fluor 594, Alexa Fluor 660, and Alexa Fluor 680; Molecular Probes, Invitrogen, Carlsbad, CA).
  • Peptide chains typically contain acidic or basic groups (such as amine or carboxyl groups) and such groups will not necessarily be in the free base form.
  • acidic or basic groups such as amine or carboxyl groups
  • the reference is intended to include salt forms of the peptide.
  • the preferred salts are pharmaceutically-acceptable salts.
  • salts embraces addition salts of free acids or free bases which are compounds of the invention.
  • pharmaceutically-acceptable salt refers to salts which possess toxicity profiles within a range that affords utility in
  • compositions of the invention may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
  • Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example,
  • ethylenediamine, meglumine (N-methylglucamine) and procaine examples include lithium salts and cyanate salts. All of these salts may be prepared from the corresponding compound according to formula I by reacting, for example, the appropriate acid or base with the compound according to formula I.
  • the compounds of the invention may be administered in the form of a pharmaceutical composition, in combination with a pharmaceutically acceptable carrier.
  • the active ingredient in such formulations may comprise from 0.1 to 99.99 weight percent.
  • “Pharmaceutically acceptable carrier” means any carrier, diluent or excipient which is compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the active agent is preferably administered with a pharmaceutically acceptable carrier selected on the basis of the selected route of administration and standard pharmaceutical practice.
  • the active agent may be formulated into dosage forms according to standard practices in the field of pharmaceutical preparations. See Alphonso Gennaro, ed., Remington 's Pharmaceutical Sciences, 18th Edition (1990), Mack Publishing Co., Easton, PA.
  • Suitable dosage forms may comprise, for example, tablets, capsules, solutions, parenteral solutions, troches, suppositories, or
  • the active agent may be mixed with a suitable carrier or diluent such as water, an oil (particularly a vegetable oil), ethanol, saline solution, aqueous dextrose (glucose) and related sugar solutions, glycerol, or a glycol such as propylene glycol or polyethylene glycol.
  • a suitable carrier or diluent such as water, an oil (particularly a vegetable oil), ethanol, saline solution, aqueous dextrose (glucose) and related sugar solutions, glycerol, or a glycol such as propylene glycol or polyethylene glycol.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active agent.
  • Stabilizing agents, antioxidant agents and preservatives may also be added. Suitable antioxidant agents include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol.
  • the composition for parenteral administration may take the form of an aqueous or non-aqueous solution, dispersion, suspension or emulsion.
  • the active agent may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, pills, powders, granules or other suitable oral dosage forms.
  • the active agent may be combined with at least one excipient such as fillers, binders, humectants,
  • the active agent may be combined with carboxymethylcellulose calcium, magnesium stearate, mannitol and starch, and then formed into tablets by conventional tableting methods.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, preferably from about 7.5 to about 500 mg.
  • unit dosage form refers to physically discrete units suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired
  • compositions of the present invention may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydropropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes and/or microspheres.
  • a controlled-release preparation is a pharmaceutical composition capable of releasing the active ingredient at the required rate to maintain constant pharmacological activity for a desirable period of time.
  • dosage forms provide a supply of a drug to the body during a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than conventional non- controlled formulations.
  • a controlled release composition of the invention provides continuous release of an active agent over a fourteen day period of time.
  • U.S. Patent No. 5,674,533 discloses controlled-release pharmaceutical compositions in liquid dosage forms for the administration of moguisteine, a potent peripheral antitussive.
  • U.S. Patent No. 5,059,595 describes the controlled-release of active agents by the use of a gastro-resistant tablet for the therapy of organic mental disturbances.
  • U.S. Patent No. 5,591,767 describes a liquid reservoir transdermal patch for the controlled administration of ketorolac, a non-steroidal anti-inflammatory agent with potent analgesic properties.
  • U.S. Patent No. 5,120,548 discloses a controlled-release drug delivery device comprised of swellable polymers.
  • U.S. Patent No. 5,639,476 discloses a stable solid controlled-release formulation having a coating derived from an aqueous dispersion of a hydrophobic acrylic polymer. Biodegradable microparticles are known for use in controlled-release formulations.
  • U.S. Patent No. 5,354,566 discloses a controlled-release powder that contains the active ingredient.
  • U.S. Patent No. 5,733,566, describes the use of polymeric microparticles that release antiparasitic compositions.
  • controlled release of the active ingredient may be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • various mechanisms of drug release exist.
  • the controlled-release component may swell and form porous openings large enough to release the active ingredient after administration to a patient.
  • controlled-release component in the context of the present invention is defined herein as a compound or compounds, such as polymers, polymer matrices, gels, permeable membranes, liposomes and/or microspheres, that facilitate the controlled-release of the active ingredient in the pharmaceutical composition.
  • the controlled-release component is biodegradable, induced by exposure to the aqueous environment, pH, temperature, or enzymes in the body.
  • sol-gels may be used, wherein the active ingredient is incorporated into a sol-gel matrix that is a solid at room temperature. This matrix is implanted into a patient, preferably a mammal, having a body temperature high enough to induce gel formation of the sol-gel matrix, thereby releasing the active ingredient into the patient.
  • compositions of the compounds of the invention that are suitable for administration intranasally or by inhalation are of particular interest.
  • the compounds of the invention can be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose in anhydrous or monohydrate form, preferably monohydrate, mannitol, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose or trehalose, or as a mixed component particle, for example, mixed with
  • phospholipids from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulae, with or without the use of a suitable propellant, such as dichlorofluoromethane.
  • atomizer preferably an atomizer using electrohydrodynamics to produce a fine mist
  • nebulae with or without the use of a suitable propellant, such as dichlorofluoromethane.
  • the pressurized container, pump, spray, atomizer, or nebulae contains a solution or suspension of the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid.
  • the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ , to 100 ⁇ L.
  • a typical formulation may comprise the compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the nicotinamide derivative of formula (I), a suitable powder base such as lactose or starch and a performance modifier such as L-leucine, mannitol, or magnesium stearate.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Sustained or controlled release can be obtained by using for example poly(D,L-lactic-co-glycolic acid).
  • a compound of the invention has "full agonist activity" of the adiponectin receptor.
  • full agonist activity means that a compound of invention demonstrates agonistic activity, but does not demonstrate antagonistic activity in the dosage form recommended, with respect to adiponectin receptor both in the presence and absence of exogenous native adiponectin or other adiponectin receptor-stimulating agents.
  • adiponectin receptor agonistic activity Compounds of the invention that bind to adiponectin receptor or that bind to and stimulate some or all of the function of adiponectin receptor (adiponectin receptor agonistic activity) may be assayed using a cellular assay as set forth in detail in Example 1 herein.
  • an adiponectin receptor binding and/or agonist assay is conducted using a cell line expressing adiponectin receptor, wherein such cells are stimulated to grow as a result of treatment with adiponectin or adiponectin analogs.
  • the skilled artisan will be aware of methods of detecting peptide-receptor binding.
  • Western blotting and dot-blotting techniques are useful for determining the binding of a compound of the invention to adiponectin receptor.
  • the skilled artisan will also be aware of methods of detecting and measuring cell growth. Cell counting, among other techniques, can be used to determine cell growth as a result of agonist activity of a compound of the present invention.
  • Other methods of measuring efficacy of compounds of the invention include, but are not limited to, receptor-binding assays, monitoring changes in downstream signaling of intracellular signaling pathways, induction of DNA and/or protein synthesis, or monitoring metabolic status of cells. Additionally, the efficacy of compounds of the invention can also be assayed in animal models, i.e., by monitoring the ability of the compounds to substitute for adiponectin in adiponectin- deficient animals, or by monitoring food intake, appetite, metabolic rates, and glucose/lipid levels in animals with obesity and insulin resistance.
  • the compounds of the invention are useful as adiponectin receptor agonists. They bind to adiponectin receptor and agonize adiponectin receptor - mediated activity, and thus, can be used for the treatment of diseases and conditions which can benefit from an adiponectin receptor -mediated upregulation in cell signaling and growth, including conditions that are related to adiponectin deficiency or adiponectin resistance. Accordingly, compounds of the invention may be used to treat conditions including, but not limited to, proliferative disorders.
  • the compounds of the invention may be used to treat conditions including, but not limited to, proliferative disorders.
  • aforementioned conditions are related to, at least in part, to adiponectin deficiency and/or adiponectin resistance.
  • an individual who is in need of treatment with a compound according to the invention can be an individual who is suffering from one or more proliferative disorders, among other disorders.
  • a method of treating an individual suffering from a cellular proliferative disorder, particularly cancer comprising administering to said individual an effective amount of at least one compound according to formula I, or a pharmaceutically acceptable salt thereof, either alone, or in combination with a pharmaceutically acceptable carrier.
  • the invention is also directed to the use in medicine of a compound according to formula I, or a pharmaceutically acceptable salt thereof.
  • the invention is also directed to the use of a compound according to formula I, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treatment of a cellular proliferative disorder, particularly cancer.
  • the invention is also directed to a compound according to formula I, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treatment of a cellular proliferative disorder, particularly cancer.
  • Particular and preferred embodiments of this aspect of the invention are those wherein the compound of formula I used in the method of treatment, either alone or as part of a composition, or as a component of the antibody conjugate, is a particular or preferred embodiment of the compound of formula I in the description of the compounds and compositions of the invention as provided herein.
  • the compounds according to the invention may be administered to individuals (mammals, including animals and humans) afflicted with a cellular proliferative disorder such as cancer, malignant and benign tumors, blood vessel proliferative disorders, autoimmune disorders, and fibrotic disorders.
  • a cellular proliferative disorder such as cancer, malignant and benign tumors, blood vessel proliferative disorders, autoimmune disorders, and fibrotic disorders.
  • the individual treated is a human.
  • malignancies including but not limited to the following: ovarian cancer; cervical cancer; breast cancer; prostate cancer; testicular cancer; lung cancer; renal cancer; colorectal cancer; skin cancer; brain cancer; leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia, and chronic lymphoid leukemia.
  • malignancies that may be treated by the compounds, compositions and methods of the invention include, but are not limited to, the following:
  • cardiac cancers including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma;
  • sarcoma e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma
  • myxoma rhabdomyoma
  • fibroma fibroma
  • sarcoma e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma
  • myxoma rhabdomyoma
  • fibroma fibroma
  • lipoma and teratoma teratoma
  • lung cancers including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma;
  • bronchogenic carcinoma e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma
  • alveolar and bronchiolar carcinoma bronchial adenoma
  • sarcoma sarcoma
  • lymphoma chondromatous hamartoma
  • mesothelioma mesothelioma
  • cancers of the esophagus e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma
  • cancers of the stomach e.g., carcinoma, lymphoma, and leiomyosarcoma
  • cancers of the pancreas e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma
  • cancers of the small bowel e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma
  • cancers of the large bowel e.g., adenocarcinoma, tubular adenoma, villous ade
  • cancers of the kidney e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia
  • cancers of the bladder and urethra e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma
  • cancers of the prostate e.g., adenocarcinoma, and sarcoma
  • cancer of the testis e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma
  • testis e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,
  • liver cancers including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma;
  • hepatoma e.g., hepatocellular carcinoma
  • cholangiocarcinoma e.g., hepatocellular carcinoma
  • hepatoblastoma hepatoblastoma
  • angiosarcoma hepatocellular adenoma
  • hemangioma hemangioma
  • bone cancers including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma malignant fibrous histiocytoma
  • chondrosarcoma chondrosarcoma
  • Ewing's sarcoma malignant lymphoma (reticulum cell sarcoma)
  • multiple myeloma malignant giant cell tumor chordoma
  • nervous system cancers including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and malignancies of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma;
  • gynecological cancers including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre-tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma
  • hematologic cancers including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplasia syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia;
  • skin cancers including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and
  • adrenal gland cancers including, for example, neuroblastoma.
  • Cancers may be solid tumors that may or may not be metastatic.
  • the term “cancer” as used herein is not limited to being of epithelial tissues only. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term “tumor cell”, as provided herein, includes a cell afflicted by any one of the above identified disorders.
  • the compounds are also believed useful in the treatment of non-cancer cellular proliferative disorders, that is, cellular proliferative disorders which are characterized by benign indications. Such disorders may also be known as
  • Non-cancer cellular proliferative disorders believed treatable by compounds according to the invention include, for example: hemangiomatosis in newborn, secondary progressive multiple sclerosis, atherosclerosis, chronic progressive myelodegenerative disease, neurofibromatosis, ganglioneuromatosis, keloid formation, Paget's disease of the bone, fibrocystic disease of the breast, uterine fibroids, Peyronie's disease, Dupuytren's disease, restenosis, benign proliferative breast disease, benign prostatic hyperplasia, X-linked lymphocellular proliferative disorder (Duncan disease), post-transplantation lymphocellular proliferative disorder (PTLD), macular degeneration, and retinopathies, such as diabetic retinopathies and proliferative vitreoretinopathy (PVR)
  • non-cancer cellular proliferative disorders believed treatable by compounds according to the invention include the presence of pre-cancerous lymphoproliferative cells associated with an elevated risk of progression to a cancerous disorder.
  • Many non-cancerous lymphocellular proliferative disorders are associated with latent viral infections such as Epstein-Barr virus (EBV) and Hepatitis C. These disorders often begin as a benign pathology and progress into lymphoid neoplasia as a function of time.
  • EBV Epstein-Barr virus
  • Hepatitis C Hepatitis C
  • Other disorders that may be treated with compounds according to formula I include type 1 diabetes, type 2 diabetes, syndrome X, obesity, impaired glucose tolerance, insulin resistance in different organs and tissues, impaired fatty-acid oxidation in different tissues, dislipidemia, lipodystrophy/lipoatrophy, cardiovascular disease such as atherosclerosis, dyslipidemia, weight loss with or without reducing food intake, rheumatoid arthritis, Crohn's disease, systemic lupus erythematosus, Sjogren's disease, cachexia, septic shock, myasthenia gravis, post- traumatic brain damage, myocardial infarction, post-surgical brain damage, and other destructive processes related to stress or activation of the inflammatory system.
  • TNF-alpha diseases or disorders comprise inflammatory disease, circulatory disease, portal hypertension, pulmonary hypertension, allergic diseases, Crohn's disease, aumoimmune haemolytic anemia, psoriasis, hepatic disease, pancreatic disease, neurodegenerative disease, central nerve failure, toxaemia, climacteric failure, gestosis, adiposis, hyperlipidemia, hypercholesteremia, abnormal glucose tolerance, solid tumor, tumor cancer and accompanying cachexia, endocrine disease, Cretuzfeldt-Jakob disease, viral infection, post-percutaneous coronary arterioplasty, vascular hypertrophy or occlusion, post-PTCA/stenting/bypass surgery vascular reocclusion/restenosis, post-intervention
  • hyperglycemia chronic obstructive pulmonary disease
  • chronic bronchitis chronic bronchitis
  • emphysema emphysema
  • Inflammatory responses that may be treated with compounds according to formula I comprise diabetic complications such as retinopathy, nephropathy, neuropathy, major vascular and microvascular disorders; arthritis such as chronic rheumatoid arthritis, osteoarthritis, rheumatoid myelitis and periosteosis,
  • Circulatory diseases that may be treated with compounds according to formula I comprise chronic heart failure including arrhythmia, angina pectoris, myocardial infarction, cardiac insufficiency and congestive heart failure,
  • arteriosclerosis including atherosclerosis, hypertension, deep vein thrombosis, occlusive peripheral circulation failure, ischemic cerebral circulation failure, disseminated intravascular coagulation syndrome, Raynaud's disease, Buerger disease.
  • Allergic diseases that may be treated with compounds according to formula I comprise asthma, allergic rhinitis, conjunctivitis, digestive tract allergy, pollinosis and anaphylaxis, chronic occlusive pulmonary disease, collagenosis.
  • Neurodegenerative diseases that may be treated with compounds according to formula I comprise Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS, encephalopathy.
  • Central nervous failure that may be treated with compounds according to formula I comprise cerebrovascular failure such as cerebral hemorrhage and cerebral infarction and its sequelae, cranial trauma, spinal damage, cerebral edema, dementia, memory failure, consciousness failure, multiple sclerosis.
  • cerebrovascular failure such as cerebral hemorrhage and cerebral infarction and its sequelae, cranial trauma, spinal damage, cerebral edema, dementia, memory failure, consciousness failure, multiple sclerosis.
  • Toxemia that may be treated with the claimed compunds comprises sepsis, septic shock, endotoxic shock, gram negative sepsis, toxin shock syndrome.
  • Endocrine disease that may be treated with compounds according to formula I comprises Addison disease, Cushing's syndrome, melanocytoma and primary aldosteronism.
  • Autoimmune disease that may be treated with compounds according to formula I comprises organ specific diseases such as thyroiditis or non-specific organ diseases such as rheumatoid and osteo-arthritis.
  • Bone disease that may be treated with compounds according to formula I comprises fracture, re-fracture, osteoporosis, osteomalacia, bone Behcet disease, ankylosing spondylitis, chronic rheumatoid arthritis and osteogonarthritis as well as articular tissue destruction in disease related thereto.
  • Neurological disorders that may be treated with compounds according to formula I comprise trauma, injury, compression to individual nerves, nerve roots, spinal cord and/or the brain, acute spinal cord and brain injury, demyelinating diseases, such as multiple sclerosis, spinal cord compression due to metastatic cancer, primary or metastatic brain tumors, chronic pain syndromes due to metastatic tumor, inflammatory CNS diseases, such as subacute sclerosing panenencephalitis,
  • Huntington's disease Guillain-Barre syndrome, Bell's palsy, diabetic neuropathy, optic neuritis, macular degeneration, retinitis pigmentosa, diabetic retinopathy, muscular dystrophy, and polymyositis-dermatomyositis.
  • Aberrant apoptosis that may be treated with compounds according to formula I comprises any virally-induced inhibition of apoptosis.
  • Complications of diabetes mellitus or stress hyperglycemia include, for example, any one or more of the following: myocardia infarction, congestive heart failure and cardiogenic shock.
  • adiponectin deficit in an individual can be readily detected in a patient by any means standard in the art, such as by measurement of systemic adiponectin levels by standard ELISA methods. The skilled artisan may be motivated to undertake such testing, for example, based on the nature of the disorder afflicting the patient.
  • the amount of the disclosed therapeutic compound that will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and is determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation also will depend on the route of administration and the seriousness of the disease, disorder, or condition and is decided according to the judgment of the practitioner and each patient's circumstances.
  • the compounds of formula I are administered by way of a continuous-release transdermal patch.
  • the compounds may be administered by any route, including oral, rectal, pulmonary, sublingual, and parenteral administration.
  • Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intravesical (e.g., to the bladder), intradermal, transdermal, topical or subcutaneous administration.
  • treatment would be given at least once per day, typically once, twice, three times or four times per day with the doses given at equal intervals throughout the day and night in order to maintain a constant presence of the drug in order to induce sufficient agonistic activity in adiponectin receptor.
  • a treatment schedule can be optimized for any given patient, and that administration of compound may occur less frequently than once per day.
  • One or more compounds of the invention may be administered
  • the compounds of the invention may also be prescribed to be taken in combination with other drugs used to treat proliferative disorders. When used in such a combination with other drugs used to treat proliferative disorders.
  • the dose of the conventional drug selected will depend on the particular compound being used and the route and frequency of administration.
  • the treatment may be carried out for as long a period as necessary.
  • treatment would be continued indefinitely while the disease state persists, although discontinuation might be indicated if the compounds no longer produce a beneficial effect.
  • the treating physician will know how to increase, decrease, or interrupt treatment based on patient response.
  • the specific dose of a compound according to the invention to obtain therapeutic benefit for treatment of a cellular proliferative disorder will, of course, be determined by the particular circumstances of the individual patient including the size, weight, age and sex of the patient, the nature and stage of the disease, the
  • a daily dosage from about 0.02 to about 50 mg/kg/day may be utilized, more preferably from about 0.1 to about 5 mg/kg/day. Higher or lower doses are also contemplated as it may be necessary to use dosages outside these ranges in some cases.
  • the daily dosage may be divided, such as being divided equally into two to four times per day daily dosing. Suitable dosage ranges for intravenous
  • administration are generally about 20-500 micrograms of active compound per kilogram body weight.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • the invention should not be construed to be limited solely to the assays and methods described herein, but should be construed to include other methods and assays as well.
  • One of skill in the art will know that other assays and methods are available to perform the procedures described herein.
  • Example 1 Identification of the active site of adiponectin and the peptide binding domain of the AdipoRl
  • adiponectin peptide fragment derivatives were synthesized in a manner in which the C-terminal carboxylic acid function was converted to an amide, -C(0)-NH 2 .
  • the peptides were synthesized on a ⁇ -alanine derivatized cleavable cellulose membrane.
  • Frank R J Immunol Methods 2002, 267(1): 13-26. All peptides thus contained an amidated C-terminal P-AlaNH 2 residue.
  • ADP 25- -AlaNH 2 (amino acids 153-162 of adiponectin): Asn-Ile-Pro-Gly-Leu-Tyr- Tyr-Phe-Ala-Tyr- -AlaNH 2 (SEQ ID NO: 7)
  • ADP 91- -AlaNH 2 D-Asn-Ile-Pro-Gly-Leu-Tyr-Tyr-Phe-Ala-D-Ser-p-AlaNH 2 (SEQ ID NO: 41)
  • ADP 157- -AlaNH 2 Asn-Ile-Pro-Nva-Leu-Tyr-Tyr-Phe-Ala-Tyr-p-AlaNH 2 (SEQ ID NO: 42)
  • ADP 223-P-AlaNH 2 Asn-Ile-Pro-Gly-Leu-Tyr-D-Ser-Phe-Ala-Tyr- -AlaNH 2 (SEQ ID NO: 43)
  • ADP 289-p-AlaNH 2 Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-Tyr-P-AlaNH 2 (SEQ ID NO: 44)
  • ADP 355-p-AlaNH 2 D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-p-AlaNH 2 (SEQ ID NO: 5)
  • ADP25- -AlaNH 2 family of peptides was assembled by Fmoc- synthesis techniques on cellulose sheets, individually cut from the solid support and cleaved from the cellulose membrane by using 2% aqueous triethyl amine overnight.
  • Peptide ADP25-p- AlaNH 2 and its modified analogs were purified by reversed-phase high performance liquid chromatography (RP-HPLC) and characterized by matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS).
  • peptide ADP 355- ⁇ 2 was lyophilized twice from 2% aqueous acetic acid solution prior to cellular efficacy studies.
  • adiponectin array peptides were individually dried down to wells of an ELISA plate, and tested for binding to biotin-labeled linear synthetic models of the 4 extracellular loops of AdipoRl .
  • the receptor/peptide binding was detected by horseradish-peroxidase conjugated streptavidin.
  • the cells were synchronized in serum-free medium (SFM) (DMEM:F12 supplemented with 0.42 g/mL bovine serum albumin, 1 mM FeS0 4 and 2 mM L-glutamine) for 24 h and then shifted back to the full growth medium containing either gAd (Phoenix Secretomics, Burlingame, CA) at 50 ng/mL, individual peptides, or no test compounds for 24 h.
  • SFM serum-free medium
  • gAd Phoenix Secretomics, Burlingame, CA
  • the cells were counted under the microscope with trypan-blue exclusion. Each experiment was performed in triplicate and repeated at least three times.
  • ADP 25- ⁇ - AlaNH 2 , ADP 91- -AlaNH 2 , ADP 157- -AlaNH 2 , ADP 223- ⁇ - ⁇ 1 3 ⁇ 4 ⁇ 2 , ADP 289- ⁇ - AlaNH 2 and ADP 355-P-AlaNH 2 were solubilized at 65°C for 30 min and were further purified by RP-HPLC and screened together with the individually synthesized adiponectin peptides at the exact concentration of 50 ng/mL.
  • peptides were identified covering the active site displayed the highest affinity to an extended version of the most N-terminal AdipoRl (loopl, sequence: Arg-Pro-Asn-Met-Tyr-Phe-Met-Ala-Pro- Leu-Gln-Glu-Lys-Val-Val (SEQ ID NO: 60)). No specific binding to other AdipoRl loops was detected.
  • the model of the globular domain of human adiponectin is a ⁇ -barrel-type structure in which the ⁇ -sheets are connected with ⁇ -loops.
  • the identified active peptide ADP 25 ⁇ P-AlaNH 2 is located on the ⁇ - ⁇ -sheet region of the protein ( Figure IB).
  • the side-chains of the C-terminal 2/3 of the identified active site are facing outside the adiponectin trimer bundle, which potentially can support interaction with and activation of AdipoRl ( Figure IB).
  • the center of the active peptide ADP 25- ⁇ - AlaNH 2 has homology only with spastin, immunoglobulin and complement proteins according to a BLAST homology search.
  • Table III Summary of structure-function analysis of adiponectin fragment derivative.
  • peptidomimetics was evaluated in MCF-7 cells as described supra and is calculated relative to the activity of gAd (baseline). Letters with a * indicate the residues where conservative modifications were made.
  • the active site of adiponectin can be characterized as a turn region followed by a ⁇ -pleated sheet fragment (Figure IB).
  • Figure IB Molecular Dynamics (MD) studies indicated that the isolated ADP 25-NH 2 loses the ⁇ -pleated sheet character and forms a series of turns ( Figure 5).
  • MD simulations the initial turn- ⁇ -sheet structure of both ADP 25-NH 2 and ADP 355-NH 2 peptides were substantially changed and showed high flexibility.
  • the backbone root mean square deviation (RMSD) values fluctuated with high frequency between 0.1 and 0.7 mm.
  • Table III summarizes the importance of individual residues in biological activity of adiponectin fragments and derivatives.
  • the results allowed identification of a highly active short active site as Ile-Pro-Gly-Leu-Tyr-Tyr-Phe-Ala (SEQ ID NO: 62). Based on structure-function analysis, the conservative substitutions in the minimal active site can be introduced at Gly 155 and Tyr 158 residues without compromising biological activity. Additions of non-natural amino acids at N- and C-termini are expected to provide stability against exopeptidase cleavage in vitro and in vivo.
  • ADP 355-NH 2 has the sequence DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer- NH 2 (SEQ ID NO: 6). The compound is based on the original ADP 25-pAla-NH 2 , and contains the minimal active site with allowed modifications (Table III).
  • ADP 25-NH 2 (amino acids 153-162 of adiponectin): Asn-Ile-Pro-Gly-Leu-Tyr-Tyr- Phe-Ala-Tyr-NH 2 (SEQ ID NO: 45)
  • ADP 91-NH 2 D-Asn-Ile-Pro-Gly-Leu-Tyr-Tyr-Phe-Ala-D-Ser-NH 2 (SEQ ID NO: 46)
  • ADP 157-NH 2 Asn-Ile-Pro-Nva-Leu-Tyr-Tyr-Phe-Ala-Tyr-NH 2 (SEQ ID NO: 47)
  • ADP223-NH 2 Asn-Ile-Pro-Gly-Leu-Tyr-D-Ser-Phe-Ala-Tyr-NH 2 (SEQ ID NO: 48)
  • ADP289-NH 2 Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-Tyr-NH 2 (SEQ ID NO: 49)
  • ADP355-NH 2 D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-NH 2 (SEQ ID NO: 6)
  • ADP25 (amino acids 153-162 of adiponectin): Asn-Ile-Pro-Gly-Leu-Tyr-Tyr-Phe- Ala-Tyr (SEQ ID NO: 50)
  • ADP223 Asn-Ile-Pro-Gly-Leu-Tyr-D-Ser-Phe-Ala-Tyr (SEQ ID NO: 53)
  • ADP289 Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-Tyr (SEQ ID NO: 54)
  • ADP355 D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser (SEQ ID NO: 3) [00209] The corresponding peptides ending with an unamidated ⁇ -Ala would be: ADP25-p-Ala (amino acids 153-162 of adiponectin): Asn-Ile-Pro-Gly-Leu-Tyr-Tyr- Phe-Ala-Tyr- -Ala (SEQ ID NO: 55)
  • ADP157-P-Ala Asn-Ile-Pro-Nva-Leu-Tyr-Tyr-Phe-Ala-Tyr-p-Ala (SEQ ID NO: 57)
  • ADP223- -Ala Asn-Ile-Pro-Gly-Leu-Tyr-D-Ser-Phe-Ala-Tyr-p-Ala (SEQ ID NO: 58)
  • ADP289- -Ala Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-Tyr-p-Ala (SEQ ID NO: 59)
  • ADP355- -Ala D-Asn-Ile-Pro-Nva-Leu-Tyr-D-Ser-Phe-Ala-D-Ser-P-Ala (SEQ ID NO: 4)
  • Example 3 Breast cancer cells express AdipoRl and respond to adiponectin and ADP 355-NH?
  • ADP 355-NH 2 Dose-dependent effects of ADP 355-NH 2 were tested in different cancer cells lines expressing AdipoRl : MCF-7, MDA-MB-231 and LN18.
  • the levels of AdipoRl were the highest in MCF-7 cells, while the receptor was less abundant in MDA-MB-231 and LN18 cells ( Figure 2A).
  • Preliminary experiments with gAd demonstrated that all cell lines are sensitive to the hormone, and maximal growth inhibition can be achieved with 50-100 ng/mL (data not shown).
  • AdipoRl appears to play a major role in transmitting antiproliferative adiponectin effects in breast cancer cells. Nakayama, S., Miyoshi, Y., Ishihara, H., Noguchi, S. (2008) Breast Cancer Res Treat 112:405-10.
  • AdipoRl expression was confirmed by Western blot (WB) in cell lines cultured in our laboratory: MDA-MB-231 (lacking estrogen receptor-a, and progesterone receptor, and expressing negligible levels of HER2), MCF7 (hormone receptor positive, moderately HER2-positive) and ZR751 (hormone receptor positive, HER2 positive) (Fig. 6)
  • MCF7 and MDA-MB-231 cells can be consistently inhibited with 50 ng/ml globular adiponectin for 24-72 h.
  • the growth inhibition level in MCF7 and MDA-MB-231 cells was 18-31% and 18-25% respectively [statistically significant (ANOVA, p ⁇ 0.05)].
  • MCF7, MDA-MB-231 (breast cancer) and LN 18 (glioblastoma) cells were used as our initial cellular models.
  • Protein loading was verified by evaluating the expression of either a constitutive enzyme glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) using 6C51 mAbs 1 : 1000 (Santa Cruz Biotechnology, CA, USA) or alpha-actin using the actin 1-19 goat polyclonal Ab (Santa Cruz) 1 : 200.
  • the following secondary Abs were used 1) donkey anti-goat IgG-HRP; 2) goat anti-mouse IgG-HRP; 3) goat anti-rabbit IgG-HRP, all applied at 1 : 1000 dilution.
  • ADP 355-NH 2 exerted differential effects on several signaling pathway depending on cell line.
  • the peptide increased the phosphorylation of AMPK at 15 and 30 min and decreased ERK1/2 phopsphorylation at 60 min.
  • ADP 355-NH 2 did not affect the activation of Akt in these cells, but it increased the phosphorylation of STAT3 at 15-60 min ( Figure 3).
  • Example 5 ADP355-NH2 exhibits superior stability in mouse serum and blood, and is not toxic in vivo
  • the neutralized supernatant was loaded on a Jupiter CI 8 RP-HPLC column (4.6 mm internal diameter, 150 mm length, 5 ⁇ particle size, 30 nm pore size; Phenomenex) that had previously been calibrated with known amounts of peptide ADP 355-NH 2 dissolved in PBS. Absorbance was measured at 214 nm. Peptide ADP 355-NH 2 was incubated at 37°C with 25% aqueous mouse serum at a final concentration of 150 ⁇ g/mL. After 0, 15, 30, 60, 120, and 240 min 95 aliquots were mixed with 25 xL 15% aqueous TCA and were incubated for 10 min at 4 °C. Sample analysis followed the protocols described above.
  • Peptide ADP 355-NH 2 was injected into 10-12 week old female CBA/J mice.
  • Bolus intraperitoneal (ip) doses were administered at 5 mg/kg, 10 mg/kg, 25 mg/kg or 50 mg/kg in sterile saline and the animals were observed for signs of systemic toxicity (tremor, head tilt, reduced activity and squinting) for 4 days.
  • On day 5 the mice were killed by C0 2 inhalation and the potential peptide elimination organs, the livers, spleens and kidneys were removed and weighed.

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Abstract

L'invention concerne des composés utiles comme agonistes de l'adiponectine selon la formule I : X-M 1 -Xaal -Ile-Pro-Xaa2-Leu-Tyr-Xaa3-Phe-Ala-Xaa4-Xaa5-M2-Z (I), dans laquelle X, M1, M2 et Z sont tels que définis selon l'invention ; dans laquelle : (a) Xaa1 représente Asn ou un acide aminé non naturel ; (b) Xaa2 représente Gly ou un acide aminé non naturel ; (c) Xaa3 représente Tyr ou un acide aminé non naturel ; (d) Xaa4 représente Tyr ou un acide aminé non naturel ; (e) Xaa5 ne représente aucun acide aminé, β-Ala ou β-AlaNH2 ; à la condition qu'au moins l'un parmi Xaa1, Xaa2, Xaa3 ou Xaa4 représente un acide aminé non naturel ; dans laquelle, lorsque le composé de la Formule I comprend un acide aminé C-terminal, ledit acide aminé C-terminal est facultativement amidé ; ou un sel de ceux-ci.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2820034A4 (fr) * 2012-02-29 2015-07-15 Ambrx Inc Polypeptides d'adiponectine modifiés et leurs utilisations
WO2020086856A1 (fr) 2018-10-24 2020-04-30 Allysta Pharmaceuticals, Inc. Formulations de peptidomimétiques d'adiponectine
WO2020136193A1 (fr) 2018-12-24 2020-07-02 Université de Mons Agonistes peptidiques du récepteur de l'adiponectine 1 et 2
WO2023106845A1 (fr) * 2021-12-08 2023-06-15 한미약품 주식회사 Nouvel analogue et conjugué d'adiponectine
JP2023541136A (ja) * 2020-09-04 2023-09-28 ソウル大学病院 ペプチド並びにそれを含む化粧料組成物及び薬学組成物

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20170141692A (ko) 2015-05-01 2017-12-26 알리스타 파마슈티컬즈, 인크. 안구 장애를 치료하기 위한 아디포넥틴 펩티드모방체
KR101838625B1 (ko) * 2016-09-20 2018-03-14 김브라이언 아디포넥틴 수용체에 대한 작용제 펩타이드
KR101967630B1 (ko) * 2017-03-03 2019-04-11 서울대학교병원 아디포넥틴 유래 펩티드 및 이를 포함하는 피부노화 방지 또는 피부주름 개선용 조성물
WO2019027910A2 (fr) 2017-07-31 2019-02-07 Myriad Genetics, Inc. Score d'activité de maladie multi-biomarqueur ajusté pour évaluaer une maladie inflammatoire
EP3848020A4 (fr) * 2018-09-03 2021-09-08 Jungjinho Effect Inc. Composition favorisant la pousse des cheveux comprenant un peptide dérivé de l'adiponectine

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002069232A2 (fr) 2001-02-19 2002-09-06 Merck Patent Gmbh Procede d'identification d'epitopes de lymphocytes t et utilisation dans la preparation de molecules a immunogenicite reduite
WO2003031586A2 (fr) 2001-10-12 2003-04-17 Human Genome Sciences Inc. Polynucleotides de type acrp30, polypeptides et anticorps
US20060052292A1 (en) 2001-12-21 2006-03-09 Maxygen Aps Maxygen Holdings, Ltd. Adiponectin fragments and conjugates
NZ534699A (en) 2002-01-18 2008-12-24 Protemix Corp Ltd Glycoisoforms of adiponectin and uses thereof
US7435808B2 (en) 2003-06-25 2008-10-14 Bristol-Myers Squibb Company Polynucleotides encoding novel adiponectin receptor variant, AdipoR2v2
CA2585733A1 (fr) * 2005-01-07 2006-07-13 Arthur J. Chirino Variants d'adiponectine
US7709607B2 (en) 2005-07-11 2010-05-04 Xencor, Inc. Adiponectin variants
US7855279B2 (en) * 2005-09-27 2010-12-21 Amunix Operating, Inc. Unstructured recombinant polymers and uses thereof

Cited By (9)

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EP2820034A4 (fr) * 2012-02-29 2015-07-15 Ambrx Inc Polypeptides d'adiponectine modifiés et leurs utilisations
WO2020086856A1 (fr) 2018-10-24 2020-04-30 Allysta Pharmaceuticals, Inc. Formulations de peptidomimétiques d'adiponectine
EP3870204A4 (fr) * 2018-10-24 2022-12-21 Allysta Pharmaceuticals, Inc. Formulations de peptidomimétiques d'adiponectine
US12201668B2 (en) 2018-10-24 2025-01-21 Allysta Pharmaceuticals, Inc. Adiponectin peptidomimetics formulations
WO2020136193A1 (fr) 2018-12-24 2020-07-02 Université de Mons Agonistes peptidiques du récepteur de l'adiponectine 1 et 2
JP2023541136A (ja) * 2020-09-04 2023-09-28 ソウル大学病院 ペプチド並びにそれを含む化粧料組成物及び薬学組成物
EP4209500A4 (fr) * 2020-09-04 2024-04-24 Seoul National University Hospital Peptide, composition cosmétique et composition pharmaceutique le comprenant
JP7511296B2 (ja) 2020-09-04 2024-07-05 ソウル大学病院 ペプチド並びにそれを含む化粧料組成物及び薬学組成物
WO2023106845A1 (fr) * 2021-12-08 2023-06-15 한미약품 주식회사 Nouvel analogue et conjugué d'adiponectine

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